Method of preparing long acting formulation

Abstract

A long acting sustained release pharmaceutical composition for dihydropyridine calcium channel blockers wherein the calcium channel blocker and a pH-dependent binde are intimately admixed in essentially spherically shaped non-rugose particles of up to 1.2 mm in diameter.

What is claimed is: 
     
       1. A method of preparing spheroids which are suitable for administration to humans and which provide long-acting sustained release of a therapeutically effective amount of dihydropyridine calcium channel blocker, which method consists essentially of; (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes about 5 to 50 weight percent of each spherical partical;   (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters;   (c) shaping the rod-shaped segments into spheroids; and   (d) drying the spheroids to obtain spheroids having area radius to circumference radius ratios in the range of 0.85 to 1.0.   
     
     
       2. The method of claim 1 in which the spheroids are formed on a rotating disc or pan. 
     
     
       3. The method of claim 1 in which the pH dependent binder is a single material, or a mixture of materials selected from either of the groups a and b consisting of: (a) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates and the partial esters thereof; and   (b) polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates and the partial esters thereof.   
     
     
       4. The method of claim 3 in which the pH-dependent binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester. 
     
     
       5. The method of claim 1 in which the dihydropyridine calcium channel blocker is a compound chosen from the group represented by the formula: ##STR7## where; R 1  is --NO 2 , --CF 3 , or halo; R 2  is alkyl or --CH 2  CH 2  OCH 3  ; and   R 6  is hydrogen or alkyl; and   R 3  is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted napthyl alkyl, or ##STR8##  in which: A is alkylene; R 4  is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and   R 5  is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof.       
     
     
       6. The method of claim 5 in which the dihydropyridine calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof. 
     
     
       7. The method of claim 6 in which the binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester. 
     
     
       8. A method of preparing spheroids which are suitable for administation to humans and which provide sustained release over a period of one day of a therapeutically effective amount, upon twice daily administration thereof when administered at successive 12-hour intervals over the period of one day, of a dihydropyridine calcium channel blocker selected from the group represented by the formula: ##STR9## where R 1  is --NO 2 , --CF 3 , or halo; R 2  is alkyl or --CH 2  CH 2  OCH 3  ; and   R 6  is hydrogen or alkyl; and   R 3  is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted napthyl alkyl, or ##STR10##  in which: A is alkylene;   R 4  is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and   R 5  is hydrogen or alkyl; and the pharmaceutically acceptable salts thereof, which method consists essentially of:     (a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder selected from (i) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates and the partial esters thereof; and   (ii) polymers and copolymers of lower alkyl acryclic acids and lower alkyl acrylates and the partial esters thereof, which binder is less soluble at a pH of less than about 4.5 and more soluble at a pH of greater than about 5.5 and wherein the binder constitutes about 5 to 50 weight percent of each spherical particle;     (b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters;   (c) shaping the rod-shaped segments into spheroids; and   (d) drying the spheroids to obtain spheroids having area radius to circumference radius ratios in the range of 0.85 to 1.0.   
     
     
       9. A method according to claim 8 wherein the dihydropyridine calcium channel blocker is nicardipine wherein, in the given formula, R 1  is --NO 2 , R 2  is --CH 3 , R 3  is --CH(CH 3 )CH 2  C 6  H 5 , and R 6  is H and pharmaceutically acceptable salts thereof. 
     
     
       10. A method according to claim 8 wherein the pH dependent binder is selected from copolymers of methacrylic acid and a lower alkyl methacrylic or acrylic acid ester. 
     
     
       11. A method according to claim 9 wherein the spheroids consist essentially of about 10 to 25 weight percent of nicardipine hydrochloride and about 5 to 25 weight percent of the pH-dependent binder selected from copolymers of methacrylic acid and methyl methacrylate, the balance being non-essential filler, binders and excipients. 
     
     
       12. A method according to claim 11 wherein the spheroids consist essentially of about 20 weight % of nicardipine hydrochloride, about 11 weight % of the methacrylic acid-methyl methacrylate copolymer, about 20 weight % of microcrystalline cellulose, about 20 weight % of maize starch, and about 29 weight % of lactose.